Advances in Dystrophinopathy Diagnosis and Therapy

Abstract

Dystrophinopathies are x-linked muscular disorders which emerge from mutations in the Dystrophin gene, including Duchenne and Becker muscular dystrophy, and dilated cardiomyopathy. However, Duchenne muscular dystrophy interconnects with bone loss and osteoporosis, which are exacerbated by glucocorticoids therapy. Procedures for diagnosing dystrophinopathies include creatine kinase assay, haplotype analysis, Southern blot analysis, immunological analysis, multiplex PCR, multiplex ligation-dependent probe amplification, Sanger DNA sequencing, and next generation DNA sequencing. Pharmacological therapy for dystrophinopathies comprises glucocorticoids (prednisone, prednisolone, and deflazacort), vamorolone, and ataluren. However, angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), and β-blockers are the first-line to prevent dilated cardiomyopathy in dystrophinopathy patients. Duchenne muscular dystrophy gene therapy strategies involve gene transfer, exon skipping, exon reframing, and CRISPR gene editing. Eteplirsen, an antisense-oligonucleotide drug for skipping exon 51 from the Dystrophin gene, is available on the market, which may help up to 14% of Duchenne muscular dystrophy patients. There are various FDA-approved exon skipping drugs including ExonDys-51 for exon 51, VyonDys-53 and Viltolarsen for exon 53 and AmonDys-45 for exon 45 skipping. Other antisense oligonucleotide drugs in the pipeline include casimersen for exon 45, suvodirsen for exon 51, and golodirsen for exon 53 skipping. Advances in the diagnosis and therapy of dystrophinopathies offer new perspectives for their early discovery and care.

Keywords: Becker muscular dystrophy; CRISPR gene editing; Duchenne muscular dystrophy; dilated cardiomyopathy; dystrophinopathies; gene drugs; gene therapy; pharmacological therapy; prime gene editing; serum creatine kinase.

Figure 1

Dystrophin gene exon structure and protein functional domains. (A) Schematic of dystrophin protein showing functional domains. Hinge (H), WW (Rsp5 domain), cysteine-rich (CYS), and carboxyl-terminal (CT) domains. Rod domain spectrin repeats are numbered 2 through 24. (B) Exons splicing patterns of the human dystrophin gene. Colors correspond to functional domains of the protein in (A). Shapes of exons indicate whether splicing between adjacent exons maintains the contiguous ORF of the protein when the shapes fit together like pieces of a puzzle. Reproduced with permission from Eric N. Olson [5].

Figure 2

The integrative physiology of muscle, bone, and adipose. Myostatin is a negative regulator of skeletal muscle and bone mass. Myostatin exerts its effects on bone mass by inhibiting bone formation through stimulating the bone resorption pathway and on muscle through the inhibition of myogenesis by downregulating the master transcription factor MyoD. However, exercise leads not only to reduction of myostatin and SOST expression, but also simultaneously increases the expression of irisin, which stimulates the bone formation pathway. While adiponectin increases bone mass, leptin reduces bone mass. The dual effect of leptin signaling on bone differs considerably between axial and appendicular regions. Image is modified from Saad 2020 [132] with License Number 5500950265743 from John Wiley and Sons.